Methods for administering weight loss medications

ABSTRACT

Methods and systems for administration of pharmaceuticals using a unit dosage package that includes a first unit dosage that has a first drug and a second drug, a second unit dosage that has the first drug and the second drug, where the second unit dosage includes a different amount of the second drug than the first unit dosage and a unit dosage package is configured to hold the first unit dosage and the second unit dosage. In preferred embodiments the methods and systems are used for administration of weight loss medications.

This application is a continuation of U.S. patent application Ser. No.12/838,364 filed on Jul. 16, 2010, which is a continuation of U.S.patent application Ser. No. 11/937,367 filed on Nov. 8, 2007, nowabandoned, which claims benefit of U.S. Provisional Application Ser. No.60/865,159, filed Nov. 9, 2006, each of which is hereby incorporated byreference in its entirety.

BACKGROUND

1. Field of the Invention

This invention relates to methods for administering pharmaceuticalcompositions, preferably, but not limited to, compositions that areuseful for affecting weight loss, suppressing appetite and/or treatingobesity-related conditions in individuals.

2. Description of the Related Art

Obesity is a disorder characterized by the accumulation of excess fat inthe body. Obesity has been recognized as one of the leading causes ofdisease and is emerging as a global problem. Increased instances ofcomplications from obesity, such as hypertension, non-insulin-dependentdiabetes mellitus, arteriosclerosis, dyslipidemia, certain forms ofcancer, sleep apnea and osteoarthritis, have been related to increasedinstances of obesity in the general population.

Prior to 1994, obesity was generally considered a psychological problem.The discovery of the adipostatic hormone leptin in 1994 brought forththe realization that in certain cases, obesity may have a biochemicalbasis. The corollary to this realization was the idea that treatment ofobesity may be achieved by chemical approaches. Since then, a number ofsuch chemical treatments have entered the market.

Various methods of treating diseases or conditions, for example, obesityand related conditions, involve administering certain drugs orcombinations thereof. For example, a number of references disclose theadministration of certain weight loss formulations that include ananticonvulsant, an opioid antagonist and/or a norepinephrine reuptakeinhibitor (NRI) to a patient in need thereof to affect weight loss. See,for example, U.S. Patent Application Publication Nos. 2004/0033965;2004/0198668; 2004/0254208; 2005/0137144; 2005/0143322; 2005/0181070;2005/0215552; 2005/0277579; 2006/0009514; 2006/0142290; 2006/0160750 and2006/0079501, all of which are hereby incorporated by reference in theirentireties.

However, the administration of certain pharmaceuticals, including butnot limited to certain weight loss formulations, at a full dosage mayinitially incur adverse side effects, such that patients may be unableto tolerate a full dosage of the indicated medication. This intolerancemay lead to more severe side effects and/or premature abandonment of theeffective dosages and/or the treatment program. For example,administering an anticonvulsant in combination with an antidepressantmay provide a combination having an enhanced ability to affect weightloss, but does not necessarily reduce or eliminate the initial adverseside effects that may accompany the administration of theanticonvulsant. Similarly, the administration of an opioid receptorantagonist in combination with an antidepressant may provide acombination having an enhanced ability to affect weight loss, but doesnot necessarily reduce or eliminate the adverse side effects that mayaccompany administration of the opioid antagonist.

SUMMARY

Methods and systems have now been developed for administering effectiveamounts of pharmaceutical formulations, preferably weight lossformulations, while reducing, minimizing and/or eliminating potentialinitial adverse side effects on the patient. In general terms, thesemethods and systems involve altering the dosage of one or morecomponents of a multi-component formulation during the course ofadministration. For example, in an embodiment, the dose of one drug in atwo-drug weight loss formulation is gradually increased from an initiallow dose to an effective maintenance dose during subsequentadministrations. In preferred embodiments, adverse side effects arereduced, and patient compliance and comfort are increased, therebyincreasing the efficacy of the treatment regimen.

An embodiment provides a method of treating a disease or condition, forexample, affecting weight loss, suppressing appetite and/or treating anobesity-related condition. The method comprises administering to apatient in need thereof a first dosage including a first drug and asecond drug; and administering a second dosage comprising the first drugand the second drug, wherein the second dosage includes a differentamount of the second drug than the first dosage.

Another embodiment provides a unit dosage package for a pharmaceuticalcomposition. The unit dosage package comprises a first unit dosageincluding a first drug and a second drug; a second unit dosagecomprising the first drug and the second drug, wherein the second unitdosage comprises a different amount of the second drug than the firstunit dosage; and a unit dosage package configured to hold the first unitdosage and the second unit dosage.

Another embodiment provides a method of packaging a combination ofbupropion and at least one of zonisamide and naltrexone. The methodcomprises providing a unit dosage package that holds the bupropion andthe at least one of the zonisamide and the naltrexone; and packagingadministration instructions with the unit dosage package in a unitdosage package.

These and other embodiments are described in greater detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other aspects of the embodiments will be readily apparent fromthe description below and the appended drawings, in which like referencenumerals refer to similar parts throughout, which are meant toillustrate and not to limit the embodiments, and in which:

FIG. 1A is a front perspective of unit cells in an embodiment of a unitdosage package.

FIG. 1B is a back perspective of unit cells in an embodiment of a unitdosage package.

FIG. 1C is a back perspective of unit cells in an embodiment of a unitdosage package.

FIG. 2A is a front perspective view of an embodiment of a unit dosagepackage with two rows of unit cells.

FIG. 2B is a back perspective of the unit dosage package in FIG. 2A.

FIG. 3A is a front perspective of an embodiment of a unit dosage packagewith two rows of unit cells.

FIG. 3B is a back perspective of the unit dosage package in FIG. 3A.

FIG. 4A is a front perspective of an embodiment of a unit dosage packageshowing four rows of unit cells.

FIG. 4B is a back perspective of the unit dosage package in FIG. 4A.

FIG. 5A is a front perspective of an embodiment of a unit dosage packagecontaining four rows of unit cells within two rows of unit cells.

FIG. 5B is a back perspective of the unit dosage package in FIG. 5A.

FIG. 6A is a front perspective of an embodiment of a unit dosage packagewith a second unit dosage package attached.

FIG. 6B is a back perspective view of the unit dosage package in FIG.6A.

FIG. 7A is a front perspective of an embodiment of a unit dosage packagecontaining six rows of unit cells and two columns of unit cells.

FIG. 7B is a back perspective of the unit dosage package in FIG. 7A.

FIG. 8A is a front perspective of an embodiment of a unit dosage packagewith a second unit dosage package attached.

FIG. 8B is a back perspective view of the unit dosage package in FIG.8A.

FIG. 9A is a front perspective view of an embodiment of a unit dosagepackage containing eight rows of blisters and two columns of unit cells.

FIG. 9B is a back perspective view of the unit dosage package in FIG.9A.

It will be understood that for the unit dosage packages described and/ordepicted herein, rows (horizontal) and columns (vertical) may beinverted so that rows become columns and columns become rows. Such aninversion is within the scope of the present disclosure although as aconvention this application generally refers to horizontal as rows andvertical as columns.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The preferred embodiments described herein relate generally to systemsand methods for administering pharmaceutical compounds for treatment ofa disease or condition, (e.g., affecting weight loss, suppressingappetite and/or treating an obesity-related condition), while reducing,minimizing and/or eliminating potential initial adverse side effects ona patient. In general terms, these methods and systems involve alteringthe dosage of one or more ingredients of a multi-ingredientpharmaceutical formulation during the course of administration. Forexample, in an embodiment, the dose of one drug in a two-drug weightloss formulation is gradually increased from an initial low dose to aneffective maintenance dose during subsequent administrations. Inpreferred embodiments, adverse side effects are reduced, patientcompliance and comfort are increased, and thereby the efficacy of thetreatment regimen is increased.

A pharmaceutical formulation comprises two or more pharmaceuticalcompositions administered either as discrete simultaneously administereddosages or as a single dosage form administration comprising two or moreactive ingredients or pharmaceutical compositions, e.g. a multilayertablet. A pharmaceutical composition is a mixture of chemical compounds(e.g. one or more drugs) with additional pharmaceutical compounds, suchas diluents or carriers. The pharmaceutical composition facilitatesadministration of the drug to an organism. Pharmaceutical compositionsmay be obtained by reacting compounds with inorganic or organic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. A “drug” as usedherein refers both to active ingredients and formulations that havereceived FDA approval as well as those that have not received FDAapproval.

In some embodiments a multilayer tablet is a pharmaceutical formulationcomprising two or more pharmaceutical layers comprising pharmaceuticalcompositions and an intermediate layer between at least two of the twoor more pharmaceutical layers. The intermediate layer is configured todissolve in vivo with a substantially higher dissolution rate than atleast two of the two or more pharmaceutical layers. Novel multilayertablet formulations are described in co-pending application entitledLAYERED PHARMACEUTICAL FORMULATIONS, filed on the same date as thepresent application, which is hereby incorporated by reference in itsentirety.

Methods of treating a disease or condition, preferably affecting weightloss, suppressing appetite and/or treating an obesity-related condition,as described herein, comprise administering a series of dosages to apatient. For example, administering a first dosage comprisesadministering a first drug and a second drug. Each drug may beadministered separately or each drug may be part of a single dosage,e.g., a capsule or multilayer tablet. Multiple techniques ofadministering a drug exist in the art including, but not limited to,oral, injection, aerosol, parenteral and topical administration.Administration of a second dosage comprises administering the first drugand the second drug. The amount of the second drug in the secondadministration is different and, in a preferred embodiment, greater thanthe amount of the second drug in the first administration. In subsequentadministrations, the amount of the second drug may be increased until aneffective maintenance dose is reached.

Some drugs may incur initial and/or severe side effects whenadministered at an effective maintenance dose. Such drugs may be coupledwith other drugs in pharmaceutical compositions to increase the efficacyor tolerability (e.g. by reducing adverse side effects) of one or bothdrugs. When such pharmaceutical formulations are administered accordingto the systems and methods described above, the side effects that mightotherwise be present during administration are reduced or eliminated.

For example, some pharmaceutical formulations for affecting weight loss,suppressing appetite and/or treating an obesity-related condition whilereducing, minimizing and/or eliminating potential initial adverse sideeffects on a patient include administration of an antidepressant inconjunction with an anticonvulsant and/or an opioid receptor antagonist.In a preferred embodiment, the pharmaceutical formulation comprising theantidepressant with the anticonvulsant or the opioid receptor antagonistis effective at treating obesity. A first dosage comprising theantidepressant with the anticonvulsant or the opioid receptor antagonistis administered on a first day. A second dosage comprising theantidepressant with the anticonvulsant or the opioid receptor antagonistis administered on a second day. The amount of the anticonvulsant or theopioid receptor antagonist in the second dosage is increased relative tothe first dosage. In each subsequent dosage, an amount of theanticonvulsant or the opioid receptor antagonist is increased until amaintenance dosage is reached. In this manner, the patient may becomeaccustomed to the administration of the dosage of the anticonvulsant orthe opioid receptor antagonist present in the pharmaceuticalformulation. The patient is then less likely to have initial and/orsevere side effects that might otherwise accompany a dosage of theanticonvulsant or the opioid receptor antagonist with the antidepressantin an amount effective to treat obesity related conditions.

For practical purposes, in some embodiments unit dosage packages areemployed to facilitate the methods described herein. Unit dosagepackages comprise pharmaceutical formulations of drugs for treating adisease or condition, preferably for affecting weight loss, suppressingappetite and/or treating an obesity-related condition. Unit dosagepackages comprise a first unit dosage comprising a first drug and asecond drug, and a second unit dosage comprising the first drug and thesecond drug. In the second unit dosage, the amount of the second drug isdifferent than the amount of the second drug in the first unit dosage.

FIG. 1A illustrates an embodiment of the unit dosage package. FIG. 1Ashows a front side 100 of unit cells 104. Each unit cell 104 contains atleast one blister 106 with a cavity that encloses a pharmaceuticalcomposition 118. The unit cell 104 contains a label 108 for a specificdose (or instructions for administering a unit dosage) contained withinthe unit cell 104. The unit cell 104 also optionally comprises a closedpush-through tab 110 and optionally a corresponding open push-throughtab 114, which has been pushed from the front side 100 of the unit cell104 to the back, to open the blister 106 and provide access to thepharmaceutical composition 118. In some embodiments, the tab is notpresent, and the dosage is pushed through the covering of the blisterpack for dispensing.

FIG. 1B shows a back side 102 of the unit dosage package. The unit cell104 in this embodiment has a label 108 for a single dose containedwithin the unit cell 104, wherein the label 108 on the back side 102corresponds to the label 108 on the front side of the unit dosagepackage 100. Shown in the embodiment of FIG. 1B is an open push-throughtab 114 before it has been peeled back or removed to open the blister106.

In FIG. 1C the back side 102 of the unit dosage package is illustratedwith an unopened unit cell 112 contrasted with an opened and peeled backpush-through tab 116 that allows dispensing of the pharmaceuticalcomposition 118 from the blister 106.

In another embodiment, FIG. 2A is a front side of a unit dosage package210 attached to a cover 206. The attached cover 206 folds to cover thefront side of the unit dosage package 210 by means of a fold 204 whichconnects the cover 206 to the unit dosage package. The unit dosagepackage 210 contains at least one blister 106 with a cavity thatprotrudes through the front of the unit dosage package 210. In someembodiments the blisters 106 are thermo-formed or cold-formed blisters.

A plurality of the blisters on unit cells is formed into rows such asthe row illustrated in FIG. 2A between the arrows 216 or the row betweenthe arrows 208. A row of blisters 216 corresponds to increasing dosagesof a specific pharmaceutical ingredient or composition. In oneembodiment a single blister 106 within a row contains a dosagecombination of an anticonvulsant and an antidepressant. The amount ofthe anticonvulsant increases in each dosage from one end of the row 208to an opposite end, while the amount of antidepressant is constant inevery dosage contained in the row 208.

Optionally, push-through tabs 202 allow for the opening of a singleblister 106 in either the row 216 or the row 208. For example, thepush-through tab 202 allows for opening the blister 106 by pushing thetab 202 from the front of the unit dosage package 210 through the backof the unit dosage package using a key, a pen, a pin, a thumbnail orsome other object. The unit dosage package is then turned over and thepush-through tab 202 is peeled away to expose and/or remove the unitdosage package backing. A dosage otherwise contained within a blister106 may then be pushed through the backing and out of the back of theunit dosage package. Alternatively, the dosage is pushed through thebacking without the optional tab. One of skill in the art willappreciate that the blisters can be on the top or bottom, and the dosagecorrespondingly pushed through the bottom or top of the package.

A unit dosage package is made of any suitable material. In someembodiments instructions for opening a unit cell are included on thecover 206 attached to the unit dosage package. Alternatively,instructions are included below the row 208, the row 216 or on any partof the front of the unit dosage package 210. In some embodimentsinstructions are separate from, but included with the unit dosagepackage as part of a kit. Instructions may also be printed on thepackaging that comes with the unit dosage package. In some embodimentsinstructions say something along these lines: (1) push-through blackhalf circle with a key, a pen or a thumbnail; (2) turn card over andpeel tab to expose foil; (3) push on plastic blister to dispense. Insome embodiments the text “PUSH” or some variation thereof is located onthe tabs which open the blisters.

FIG. 2B illustrates the back of a unit dosage package 214. The back ofthe unit dosage package 214 is made of any suitable material for a unitdosage package. For example, the backing 212 of each blister 106 maycomprise a semi-rigid foil or other material connected to the tab 202and also to the blister 106. As explained previously, when the tab 202is pushed through from the front of the unit dosage package to the backof the unit dosage package, the tab 202 is then peeled back, peelingaway the backing 212 to expose and/or allow for the pharmaceuticalcomposition to be pushed out of the blister 106. Alternatively, the tabis omitted and the dosage is pushed through the backing without firstpeeling it back.

In some embodiments multiple drugs are contained within a single blisterfor release at a specific time. In other embodiments, a single blistercontains only a single drug, for example, a single dose of one or moreimmediate-release formulations. The term “immediate-release” is usedherein to specify that the immediate release formulation is notconfigured to alter the dissolution profile of the formulation. In someembodiments the one or more formulations comprise one or morecontrolled-release formulations. The term “controlled-release” is usedherein in its ordinary sense and thus includes formulations that arecombined with ingredients to alter their dissolution profile. A“sustained-release” formulation is a type of controlled-releaseformulation, wherein ingredients have been added such that thedissolution profile is extended over a longer period of time than thatof an immediate release formulation. A “unit dosage” is an amount ofdrug or drugs taken at a single dosage time. In some embodiments a unitdosage comprises a combination of drugs in a single pharmaceuticalformulation or physical form, e.g. a pill or capsule. In someembodiments a unit dosage comprises a combination of drugs in aplurality of separate pharmaceutical formulations or physical forms,e.g. multiple pills or capsules. In some embodiments a single drug ispresent in a plurality of pharmaceutical formulations or physical forms,e.g. pills or capsules, as a single unit dosage. In some embodiments aunit dosage may be contained within one or more blisters. Thus, in someembodiments, a single blister contains only a single drug, for example,a single dose of sustained-release zonisamide in a single pill orcapsule. In other embodiments, a unit dosage of sustained-releasezonisamide may be contained within multiple blisters, for example, eachcontaining one or more pills. Thus, in one embodiment two or three ofthe blisters within a single row or column in a unit dosage packagecomprise a single unit dosage of a drug.

FIG. 3A illustrates an embodiment wherein a day label 302 correspondswith a time label 304. The day label 302 additionally corresponds to aunit cell 104 containing a unit dosage. In this embodiment a singleblister 106 is contained within a unit cell 104. In the illustratedembodiment a row of blisters 308 corresponds to a specific time label304 for administration of a medication. As shown in FIG. 3A, a certainday 302 corresponds to a particular administration of one or more unitdosages to a patient. For example, from row 308 and column 306 a firstunit dosage corresponds to an AM administration on a Saturday. Laterthat same day, from row 310 and column 306 (for administration in anevening time), a patient receives a second unit dosage. Thus, a patientuses the unit dosage package to administer the particular drugs foraffecting obesity.

In some embodiments, a pharmaceutical composition corresponding to aunit dosage includes a plurality of drugs. In those embodiments, aspecific day 302 and time 304 corresponds to a single unit dosage. Forexample, in one embodiment of a series of unit dosages each dosagecomprises a static amount of a first drug and a static amount of asecond drug. In another embodiment of a series of unit dosages eachdosage comprises a static amount of a first drug and varying dosages ofa second drug. In another embodiment of a series of unit dosages eachdosage comprises a varying amount of a first drug and a varying amountof a second drug.

In some embodiments, unit dosages on a unit dosage package aresequentially numbered, lettered, or a combination of numbers and lettersto indicate an order of administration of each unit dosage. In someembodiments the sequential numbering corresponds to 1, 2, 3, 4, 5, 6, 7,8, 9, 10, . . . n, wherein each number corresponds to a part of, orwhole day, week, or month, where “n” is a finite number. For example, inone embodiment, a unit dosage package similar in form to FIG. 3Acomprises numerical labels corresponding to the days and times ofadministration. In this embodiment, no “day labels” or “time labels” arepresent.

FIG. 3B illustrates a back of the unit dosage package illustrated inFIG. 3A.

In another embodiment of a unit dosage package FIG. 4A illustrates aseries of push-through tabs 402 for opening a plurality of blisters 106.For example, within column 412, blisters from both row 404 and row 406would be opened by pulling on tab 414 to remove a backing 416 discussedbelow with reference to FIG. 4B. Similarly, push-through tab 418 wouldopen two blisters 106 within column 412, one from row 408 and one fromrow 410.

FIG. 4B illustrates the backing 416 for the unit dosage package in FIG.4A. The backing 416 allows for a push-through tab 402 to open multipleblisters at a single time.

In another embodiment of a unit dosage package illustrated in FIG. 5A,specific day labels 302 on unit cells 104 each correspond to a timelabel 304 for administration of medication. Here, the time labels 304shown for administration of medication are AM and PM administrations. Inan AM administration, a unit cell 104 comprises a single blister 106from row 502 and a single blister 106 from row 504. A row of unit cells104 corresponds to evening administration. Thus, in this embodiment,each unit cell 104 within row 506 contains two blisters 106 for eveningadministration of a specific pharmaceutical composition.

Further, a unit dosage comprising a combination of drugs within column508 corresponds to a morning administration and an eveningadministration on a Saturday. The morning administration comprises oneblister 106 from row 502 and one blister 106 from row 504. Thecombination of medications from rows 502, 504 correspond to a unitdosage of medication for administration on a Saturday morning.

FIG. 5B illustrates a back of the unit dosage package illustrated inFIG. 5A.

Another embodiment of a unit dosage package is illustrated in FIG. 6A.The embodiment shows a second unit dosage package 602 attached to afirst unit dosage package 601 via a fold 610. The first unit dosagepackage 601 illustrates a row 604 comprising four blisters 106 wherein asingle push-through tab 606 that opens all blisters 106 within the row604. Similarly, the second unit dosage package 602 contains multipleblisters 106 arranged into rows and columns. A push-through tab 612 foropening a row of blisters 106 is shown on the second unit dosage package602. The push-through tab 612 would open an entire row, for example, therow 608 on the second unit dosage package 602.

As illustrated in FIG. 6A, a row of blisters 608 on the second unitdosage package 602 contains two blisters 106. A row of blisters 604 onthe first unit dosage package 601 contains four blisters. Thus, in someembodiments a single unit dosage package comprises numerous blisters106. Further, as illustrated in FIG. 6A, each row of blisters 106 isconfigured to be opened by the push-through tabs 606 or 612.

FIG. 6B corresponds to a back side of the unit dosage packageillustrated in FIG. 6A.

Another embodiment of a unit dosage package is illustrated in FIG. 7A.Similar to the embodiment illustrated in FIG. 6A, a first unit dosagepackage 601 is attached to a second unit dosage package via a fold 610.The first unit dosage package 601 is also attached to a cover 206 via afold 204. In some embodiments the cover comprises an instruction sheet.In this embodiment, the first unit dosage package 601 corresponds to AMadministration of unit dosages and the second unit dosage package 602corresponds to PM administration of unit dosages.

FIG. 7B illustrates the back side of the unit dosage package in FIG. 7A.

Similar to the embodiment illustrated in FIG. 7A, FIG. 8A illustratesone embodiment comprising a first unit dosage package 601 attached to acover 206 via fold 204. The first unit dosage package 601 is alsoattached to a second unit dosage package 602 via fold 610. Here, thesecond unit dosage package 602 comprises a row 804 of four blisters 106wherein a single row of blisters 106 are opened by a single push-throughtab 612. FIG. 8A illustrates that a single push-through tab 612 opensall four blisters 106 within a row 804 on the second unit dosage package602. Similarly, a single push-through tab 606 opens the row 804 ofblisters 106 on the first unit dosage package 601.

FIG. 8B illustrates a back of the unit dosage package in FIG. 8A.

In another embodiment illustrated in FIG. 9A, the first unit dosagepackage 601 attached to a cover 206 via a fold 204 corresponds to a timelabel 304, specifically an AM administration of a drug. The AM dosagesfor an extra week are arranged in unit cells 104 on the first unitdosage package 601. As in FIG. 8A, opening a single push-through tab 606exposes drugs contained within a row 604 corresponding to a unit dosageof an AM administration on a Thursday. Similarly, a push-through tab 612opens all blisters 106 in a unit cell 104 corresponding to the row 804on Saturday evening. Each day and time listed on the first unit dosagepackage 601 and the second unit dosage package 602 corresponds todifferent dosages.

FIG. 9B illustrates the back side of the unit dosage package illustratedin FIG. 9A.

In any of the embodiments disclosed herein, the active pharmaceuticalingredients utilized to treat a disease or condition can be selectedfrom any of the compounds below.

Antidepressants and Psychotherapeutics

As mentioned previously, in some embodiments the compositions for thetreatment of obesity or for affecting weight loss comprise anantidepressant and at least one of an anticonvulsant and an opioidreceptor antagonist. In some embodiments the antidepressant comprises adopamine reuptake inhibitor or receptor antagonist. Examples of dopaminereuptake inhibitors include phentermine and pharmaceutically acceptablesalts or prodrugs thereof. Examples of dopamine receptor antagonistsinclude haloperidol, ocaperidone, risperidone, olanzapine, quetiapine,amisulpride, and pimozide and pharmaceutically acceptable salts orprodrugs thereof. In some embodiments the antidepressant comprises anorepinephrine reuptake inhibitor. Examples of norepinephrine reuptakeinhibitors include bupropion, thionisoxetine, atomoxetine and reboxetineand pharmaceutically acceptable salts or prodrugs thereof. Otherembodiments include those in which the antidepressant is a dopamineagonist. Dopamine agonists available on the market include cabergoline,amantadine, lisuride, pergolide, ropinirole, pramipexole, andbromocriptine. In some embodiments the antidepressant comprises aserotonin reuptake inhibitor, preferably a selective serotonin reuptakeinhibitor (SSRI). Examples of serotonin reuptake inhibitors includefluoxetine and pharmaceutically acceptable salts or prodrugs thereof.

Throughout the disclosure of the present specification the term“pharmaceutically acceptable salt” refers to a formulation of a compoundthat does not cause significant irritation to an organism to which it isadministered and does not abrogate the biological activity andproperties of the compound. Pharmaceutical salts can be obtained byreacting a compound of the disclosure with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticalsalts can also be obtained by reacting a compound of the disclosure witha base to form a salt such as ammonium salt, an alkali metal salt suchas a sodium or a potassium salt, an alkaline earth metal salt such as acalcium or a magnesium salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamineand salts thereof with amino acids such as arginine, lysine and thelike.

The term “prodrug” refers to an agent that is converted into the parentdrug in vivo. Prodrugs are often useful because, in some situations,they are easier to administer than the parent drug. They can, forinstance, be bioavailable by oral administration whereas the parent isnot. The prodrug can also have improved solubility in pharmaceuticalcompositions over the parent drug or can demonstrate increasedpalpability or be easier to formulate.

Bupropion, whose chemical name is(±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone, is theactive drug in the drugs marketed as ZYBAN® and WELLBUTRIN®, and isusually administered as a hydrochloride salt. Throughout the presentdisclosure, whenever the term “bupropion” is used, it is understood thatthe term encompasses bupropion as a free base, or as a physiologicallyacceptable salt thereof, or as a bupropion metabolite or salt thereof.

The metabolites of bupropion suitable for inclusion in the methods andcompositions described herein include the erythro- and threo-aminoalcohols of bupropion, the erythro-amino diol of bupropion, andmorpholinol metabolites of bupropion. In some embodiments, themetabolite of bupropion is(±)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol. In someembodiments the metabolite is(−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol, while inother embodiments, the metabolite is(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol.Preferably, the metabolite of bupropion is(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol, which isknown by its common name of radafaxine. The scope of the presentdisclosure includes the above-mentioned metabolites of bupropion as afree base or as a physiologically acceptable salt thereof.Controlled-release bupropion formulations of bupropion are known in theart. See, for example, U.S. Pat. No. 6,905,708, which discloses aonce-daily dosage configured to deliver bupropion in vivo over a 6 to 12hour period.

Olanzapine, whose chemical name is2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,is used as a psychotherapeutic agent primarily for the treatment ofschizophrenia, acute manic episodes in bipolar disorder acute,maintenance treatment in bipolar disorder and agitation associated withboth these disorders. Throughout the present disclosure, whenever theterm “olanzapine” is used, it is understood that the term encompassesolanzapine as a free base, or as a physiologically acceptable saltthereof, or as a olanzapine metabolite or salt thereof.

Olanzapine displays linear kinetics. Its elimination half-life rangesfrom 21 to 54 hours. Steady state plasma concentrations are achieved inabout a week. Olanzapine undergoes extensive first pass metabolism andbioavailability is not affected by food.

The psychotherapeutic agent may be selected from the group consisting ofmirtazapine, setiptiline, paroxetine, venlafaxine, olanzapine,bupropion, risperidone, lamotrogine, risperidone, a lithium salt,valproic acid, and pharmaceutically acceptable salts or prodrugsthereof. In some embodiments the psychotherapeutic agent is anantidepressant, an antimigrane, an antibipolar, an antimania drug, amood stabilizer, or an antiepileptic. Examples of antidepressantsinclude paroxetine, mirtazapine, and bupropion. Examples of antibipolardrugs include lithium, valproate, carbamezepine, oxycarbamezepine,lamotrogine, tiagabine, olanzapine, clozapine, risperidone, quetiapine,aripiprazole, ziprasidone, and benzodiazepines. Also included arepharmaceutically acceptable salts or prodrugs of these drugs, extendedrelease or controlled release formulations of the above drugs, as wellas combinations of the above drugs.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI), whosechemical name isN-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-1-amine, is usedprimarily for the treatment of depression (including pediatricdepression), obsessive-compulsive disorder (in both adult and pediatricpopulations), bulimia nervosa, panic disorder, premenstrual dysphoricdisorder, hypochondriasis and body dysmorphic disorder. Throughout thepresent disclosure, whenever the term “fluoxetine” is used, it isunderstood that the term encompasses fluoxetine as a free base, or as aphysiologically acceptable salt thereof, or as a fluoxetine metaboliteor salt thereof.

Fluoxetine has a bioavailability of approximately 72%, and peak plasmaconcentrations are reached in 6 to 8 hours. It is highly bound to plasmaproteins, mostly albumin. Its elimination half-life ranges from 1 to 3days—after a single dose—to 4 to 6 days (after long-term use) in healthyadults, and is prolonged in those with liver disease. The half-life ofnorfluoxetine is longer (16 days after long-term use). Completeexcretion of the drug may take several weeks.

The SSRI can be selected from fluoxetine, fluvoxamine, sertraline,paroxetine, citalopram, escitalopram, sibutramine, duloxetine, andvenlafaxine, and pharmaceutically acceptable salts or prodrugs thereof.In some embodiments, the SSRI is fluoxetine or a pharmaceuticallyacceptable salt or prodrug thereof.

Fluoxetine has a physiological half life of about 24 hours, whereas thatof naltrexone is about 1.5 hours. However their metabolites maydemonstrate half-lives in excess of 24 hours. Thus, in some cases, itmay be beneficial to administer one dose of fluoxetine per day inconjunction with two or three or more doses of naltrexone (discussedbelow) throughout the day. Naltrexone may also be in a time-releaseformulation where the dose is administered once a day, but naltrexonegradually enters the blood stream throughout the day, or in the courseof a 12 hour period.

Symptoms of the obsessive compulsive disorders are inhibited inindividuals being administered fluoxetine and naltrexone. Adverse eventsassociated with the obsessive compulsive disorders are reduced inindividuals being administered fluoxetine and naltrexone. The effects ofadministration of both fluoxetine and naltrexone on obsessive compulsivedisorder are synergistic compared to effects of those expected byadministration of fluoxetine and naltrexone alone.

Newer generation antidepressants include selective serotonin reuptakeinhibitors (e.g., fluoxetine, fluvoxamine, sertraline, paroxetine,citalopram, and escitalopram), venlafaxine, duloxetine, nefazodone,mianserin setiptiline, viqualine trazodone, cianopramine, andmirtazapine.

Phentermine is an example of a dopamine reuptake inhibitor with achemical name 2-methyl-1-phenylpropan-2-amine and 2-methyl-amphetamine.Throughout the present disclosure, whenever the term “phentermine” isused, it is understood that the term encompasses phentermine as a freebase, or as a physiologically acceptable salt thereof, or as aphentermine metabolite or salt thereof.

Antidiabetic

In some embodiments an antidiabetic comprises a biguanide, glucosidaseinhibitor, insulin, meglitinide, sulfonylurea or a thiazolidinedione. Insome embodiments a biguanide comprises metformin hydrochloride. In someembodiments a glucosidase inhibitor includes acarbose and miglitol.Examples of insulin include human insulin, pork insulin, beef insulin,beef-pork insulin, insulin from different sources such as recombinantDNA and animal sources, as well as regular, NPH, and LENTE® types ofinsulin. Other examples of insulin include mixtures of the various formsof insulin (e.g. NPH and regular human and pork insulin). Other examplesof insulin include mixtures of Insulin Lispro Protamine and InsulinInjection (rDNA origin), a 50/50 (or a 70/30) mixture of Human InsulinIsophane Suspension and Human Insulin Injection, a 70/30 mixture of NPHHuman Insulin Isophane Suspension and Human Insulin Injection (rDNA),insulin glargine, insulin lispro, insulin aspart, as well as insulinmixed with other ingredients such as zinc crystals or in a phosphatebuffer. Insulin may be from Saccharomyces cerevisiae or other sources.Examples of meglitinides include nateglinide and repaglinide. Examplesof sulfonylureas include glimepiride, glyburide, glibenclamide,gliquidone, gliclazide, chlorpropamide, tolbutamide, tolazamide andglipizide. Examples of thiazolidinediones include rosiglitazone andpioglitazone. Also included are extended release formulations of theabove drugs, as well as combinations of the above drugs andpharmaceutically acceptable salts or prodrugs thereof.

As mentioned above, in certain embodiments, the antidiabetic ismetformin. Metformin, whose chemical name is1-(diaminomethylidene)-3,3-dimethyl-guanidine, is often used in thetreatment of diabetes mellitus type 2, especially when accompaniedobesity and insulin resistance. Metformin has also been proven to reducethe cardiovascular complications of diabetes.

Anticonvulsants

In some embodiments, the anticonvulsant is selected from the groupconsisting of zonisamide, topiramate, nembutal, lorazepam, clonazepam,clorazepate, tiagabine, gabapentin, fosphenyloin, phenyloin,carbamazepine, balproate, felbamate, lebetiracetam, oxcarbazepine,lamotrigine, methsuximide and ethosuxmide.

Zonisamide is a marketed anticonvulsant indicated as adjunctive therapyfor adults with partial onset seizures. Without being bound by anyparticular theory, it is believed that the mechanism of antiepilepticactivity appears to be: (1) sodium-channel blocking; and (2) reductionof inward T-type calcium occurrence. In addition, zonisamide binds tothe GABA/benzodiazepine receptor complex without producing change inchloride flux. Further, zonisamide facilitates serotonergic anddopaminergic neurotransmission and possesses a weak inhibitory effect oncarbonic anhydrase.

Zonisamide has been shown to cause significant weight loss (comparableto marketed weight loss medications) in patients presenting primaryobesity. It has been postulated that the affect of zonisamide on the CNSconcentration of serotonin, dopamine and carbonic anhydrase isresponsible for this effect. There is evidence that zonisamide increasesserotonin and dopamine synthesis rates herein. There is further evidencesuggesting that zonisamide stimulates dopamine D₂ receptors.

Zonisamide can be formulated in an immediate release, acontrolled-release and/or sustained-release tablet or gel form. Thisallows a patient newly prescribed zonisamide to ramp up the dosage levelover a period of several days. This increase in dosage form allows thepatient to avoid some of the negative side effects that have beenexhibited during the initial administration of zonisamide to a patient.Some of these initial side effects include a shock to the body. Althoughpatients who start with a full dose of zonisamide will become acclimatedto the dosage over a period of time, the negative side effectsaccompanying the initial shock to the body can be avoided with a methodwherein dosages are increased over a period of several days.

In a pharmaceutical formulation with a drug such as bupropion, a methodof administering sustained-release zonisamide by increasing dosages overa period of time can reduce shock to the body while still having amaximum effect for prevention of weight gain and/or treatment ofobesity.

In some embodiments, the antidepressant and the anticonvulsant areadministered more or less simultaneously. In other embodiments, theantidepressant is administered prior to the anticonvulsant. In yet otherembodiments, the antidepressant is administered subsequent to theanticonvulsant.

In certain embodiments, the antidepressant and the anticonvulsant areadministered individually. In the other embodiments, the first compoundand the anticonvulsant are covalently linked to each other such thatthey form a single chemical entity. The single chemical entity is thendigested and is metabolized into two separate physiologically activechemical entities, one of which is the antidepressant and the other oneis the anticonvulsant.

Pharmaceutical preparations of the types found in the unit dosagepackages of the present disclosure include forms suitable for packagingwithin a blister including gel capsules and tablets.

Although the exact dosages will be determined on a drug-by-drug basis,in most cases some generalizations regarding the dosage can be made.Some descriptions of appropriate unit dosages of bupropion, zonisamide,and combinations thereof are disclosed in U.S. Provisional PatentApplication Nos. 60/740,034, filed on Nov. 28, 2005; 60/832,110, filedon Jul. 19, 2006; 60/835,564, filed on Aug. 4, 2006; and U.S. patentapplication Ser. No. 11/194,201 entitled COMBINATION OF BUPROPION AND ASECOND COMPOUND FOR AFFECTING WEIGHT LOSS, filed on Aug. 1, 2005; whichare hereby incorporated by reference in their entireties, and U.S.Patent Publication Nos. 2005/0215552; and 2006/0079501 mentionedpreviously.

In some embodiments the anticonvulsant is a γ-amino butyric acid (GABA)inhibitor, a GABA receptor antagonist or a GABA channel modulator. By“GABA inhibitor” it is meant a compound that reduces the production ofGABA in the cells, reduces the release of GABA from the cells, orreduces the activity of GABA on its receptors, either by preventing thebinding of GABA to GABA receptors or by minimizing the effect of suchbinding. The GABA inhibitor may be a 5-HT1b agonist or another agentthat inhibits the activity of NPY/AgRP/GABA neurons. In addition, theGABA inhibitor may suppress the expression of the AgRP gene, or the GABAinhibitor may suppress the production or release of AgRP. It is,however, understood that a 5-HT1b agonist may inhibit the NPY/AgRP/GABAneuron (and therefore activate pro-opiomelanocortin (POMC) neurons)without acting as an inhibitor of the GABA pathway.

In certain other embodiments the GABA inhibitor increases the expressionof the POMC gene. In some of these embodiments, the GABA inhibitorincreases the production or release of POMC protein. In certain other ofthese embodiments, the GABA inhibitor increases the activity on POMCexpressing neurons.

In some embodiments, the GABA inhibitor is topiramate. Topiramate, whosechemical name is2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate, isoften used to treat epilepsy, Lennox-Gastaut syndrome (a disordercausing seizures and developmental delays), neuropathic pain, bipolardisorder, obesity including reduction of binge eating, alcoholism, PostTraumatic Stress Disorder, infantile spasm, bulimia nervosa, orobsessive-compulsive disorder or to assist smoking cessation or preventmigraines. Generally, initial doses of topiramate are low and increasedin slow steps. The usual initial dose is 25 to 50 mg daily in 2 singledoses. Recommended increments vary, but are usually between 25 mg and 50mg every 1 or 2 weeks. Common doses for maintenance treatment are 100 to200 mg daily.

Opioid Receptor Antagonists

In certain embodiments the opioid antagonist antagonizes a μ-opioidreceptor (MOP-R) in a mammal. The mammal may be selected from the groupconsisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep,goats, cows, primates, such as monkeys, chimpanzees, and apes, andhumans.

In some embodiments the opioid antagonist is selected from the groupconsisting of alvimopan, norbinaltorphimine, nalmefene, naloxone,naltrexone, methylnaltrexone, and nalorphine, and pharmaceuticallyacceptable salts or prodrugs thereof.

In other embodiments, the opioid antagonist is a partial opioid agonist.Compounds of this class have some agonist activity at opioid receptors.However, because they are weak agonists, they function as de-factoantagonists. Examples of partial opioid agonists include pentacozine,buprenorphine, nalorphine, propiram, and lofexidine.

Naltrexone(17-(cyclopropylmethly)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) is anopioid receptor antagonist used primarily in the management of alcoholdependence and opioid dependence. μ-subtype selective opioid antagonistssuch as naltrexone are also of considerable current interest as agentsfor the treatment of obesity (Glass, M. J.; Billington, C. J.; Levine,A. S. Neuropeptides 1999, 33, 350) and CNS disorders (Reneric, J. P.;Bouvard, M. P. CNS Drugs 1998, 10, 365).

Naltrexone is marketed as its hydrochloride salt, naltrexonehydrochloride, under the trade name REVIA™. REVIA™ is an immediaterelease formulation of naltrexone, with 50 mg strength. The maximumserum concentration of immediate release naltrexone is reached veryrapidly, typically a T_(max) of approximately 1 hour. Immediate releasenaltrexone can induce side effects such as nausea, which is attributableto the maximum blood plasma concentration levels (C_(max)).

Formulations of sustained-release naltrexone have been disclosed in U.S.Provisional Patent Application Ser. Nos. 60/811,251, filed Jun. 5, 2006;and 60/841,114, filed Aug. 29, 2006; which are hereby incorporated byreference in their entireties. In some embodiments, oral dosage forms ofnaltrexone are effective to provide an AUC between about 75% to about125% of 50 mg immediate release naltrexone tablets. In some embodimentsoral dosage forms of naltrexone provide an amount of a retardantexcipient that is effective to provide a C_(max) that is less than orequal to about 80% of the C_(max) of 50 mg immediate release naltrexonetablets.

Those skilled in the art informed by the guidance provided herein canformulate oral dosage forms described herein. For example, one skilledin the art could formulate an oral dosage form that comprises an amountof naltrexone that is effective to provide an AUC between about 75% toabout 125% of 50 mg immediate release naltrexone tablets, and an amountof an appropriate retardant excipient effective to provide a C_(max)that is less than or equal to about 80% of the C_(max) of 50 mgimmediate release naltrexone tablets. Further, given the guidanceprovided herein, the skilled artisan could formulate an oral dosage formhaving a pharmacodynamic profile characterized by coverage of greaterthan or equal to about 80% of the opioid receptors in the hypothalamus.

Sustained-Release Zonisamide and Sustained-Release Bupropion

A pharmaceutical formulation comprising sustained-release zonisamide andbupropion can be made in various ways, e.g., by intermixing granules orbeads of sustained-release zonisamide with bupropion orsustained-release bupropion, then forming tablets from the mixture inthe usual fashion.

A pharmaceutical formulation of zonisamide in combination with bupropioncan be used to treat various conditions. For example, an embodimentprovides a method for affecting weight loss, increasing energyexpenditure, increasing satiety in an individual, and/or suppressing theappetite of an individual, comprising identifying an individual in needthereof and administering effective amounts of sustained-releasezonisamide and bupropion. In some embodiments the sustained-releasezonisamide and bupropion are administered more or less simultaneously.In other embodiments the sustained-release zonisamide is administeredprior to the bupropion. In yet other embodiments, the sustained-releasezonisamide is administered subsequent to the bupropion. In otherembodiments, one of the compounds is administered while the othercompound is being administered.

Sustained-Release Zonisamide and Sustained-Release Naltrexone

In some embodiments naltrexone comprises formulations of eitherimmediate release naltrexone or sustained-release naltrexone. Apharmaceutical formulation comprising sustained-release zonisamide andnaltrexone can be made in various ways, e.g., by intermixing granules orbeads of sustained-release zonisamide with naltrexone orsustained-release naltrexone, then forming tablets from the mixture inthe usual fashion.

Sustained-release zonisamide pharmaceutical formulation can be used incombination with naltrexone to treat various conditions. For example, anembodiment provides a method for affecting weight loss, increasingenergy expenditure, increasing satiety in an individual, and/orsuppressing the appetite of an individual, comprising identifying anindividual in need thereof and administering effective amounts ofsustained-release zonisamide and naltrexone. In some embodiments thesustained-release zonisamide and naltrexone are administered more orless simultaneously. In other embodiments the sustained-releasezonisamide is administered prior to the naltrexone. In yet otherembodiments, the sustained-release zonisamide is administered subsequentto the naltrexone. In other embodiments, one of the compounds isadministered while the other compound is being administered.

Sustained-Release Bupropion and Sustained-Release Naltrexone

In some embodiments naltrexone comprises formulations of eitherimmediate release naltrexone or sustained-release naltrexone. In someembodiments bupropion comprises formulations of either immediate releaseor sustained-release bupropion. A pharmaceutical formulation comprisingboth bupropion and naltrexone is used in various disclosed embodiments.

Sustained-release bupropion can be used in a pharmaceutical formulationwith naltrexone to treat various conditions. For example, an embodimentprovides a method for affecting weight loss, increasing energyexpenditure, increasing satiety in an individual, and/or suppressing theappetite of an individual. The method comprises identifying anindividual in need thereof and administering effective amounts ofsustained-release bupropion and naltrexone in a pharmaceuticalformulation. In some embodiments the bupropion and naltrexone areadministered more or less simultaneously. In other embodiments thebupropion is administered prior to the naltrexone. In yet otherembodiments, the bupropion is administered subsequent to the naltrexone.In other embodiments, one of the compounds is administered while theother compound is being administered.

Embodiments

In one embodiment a method of treating a disease or condition comprisesidentifying a patient suffering from or at risk of said condition. Insome embodiments the disease or condition is selected from the groupconsisting of affecting weight loss, suppressing appetite and treatingan obesity-related condition. In one embodiment the method comprisesadministering to a patient in need thereof a first dosage comprising afirst drug and a second drug and administering a second dosagecomprising the first drug and the second drug, wherein the second dosagecomprises a different amount of the second drug than the first dosage.

In some embodiments the second dosage comprises a greater amount of thesecond drug than the amount of the second drug in the first dosage. Inother embodiments the second dosage comprises a smaller amount of thesecond drug than the first dosage. In some embodiments the second dosagecomprises a different amount of the first drug than the first dosage. Insome embodiments the first drug comprises a greater amount in the seconddosage than in the first dosage. In other embodiments the first drugcomprises a smaller amount in the second dosage than in the firstdosage. In some embodiments the first drug comprises a greater amount inthe second dosage than in the first dosage and the second drug comprisesa greater amount in the second dosage than in the first dosage. In someembodiments the first drug comprises a greater amount in the seconddosage than in the first dosage and the second drug comprises a smalleramount in the second dosage than in the first dosage. In someembodiments the first drug comprises a smaller amount in the seconddosage than in the first dosage and the second drug comprises a smalleramount in the second dosage than in the first dosage. In any of theembodiments, the change in amount of the first and/or second drug can becontinued in the third, fourth, fifth, sixth, seventh or more dosages,until the desired amount is reached, at which point the amount ismaintained in subsequent doses. The number of doses which haveincreasing or decreasing amounts of one drug can be different or thesame as the number of doses which have increasing or decreasing amountsof the other drug. One of skill in the art will recognize that theembodiments described herein are not limited to two drug combinations,but can include 3, 4, 5, 6, or more drugs, each independentlyincreasing, decreasing or maintaining the amount of drug in dose.

In some embodiments the obesity-related condition is at least oneselected from obesity, hypertension, diabetes, dyslipidaemia,hyperglycemia, weight gain associated with smoking cessation, and weightgain associated with use of a psychotherapeutic drug. In someembodiments the second dosage comprises a greater amount of the seconddrug than the first dosage. In some embodiments the first drug comprisesan antidepressant. In some embodiments the antidepressant comprisesbupropion. In some embodiments the bupropion comprises acontrolled-release bupropion. In some embodiments the controlled-releasebupropion comprises a sustained-release bupropion. In some embodimentsthe second drug comprises an anticonvulsant. In some embodiments theanticonvulsant comprises zonisamide. In some embodiments the zonisamidecomprises a controlled-release zonisamide. In some embodiments thecontrolled-release zonisamide comprises a sustained-release zonisamide.In some embodiments the second drug comprises an opioid antagonist. Insome embodiments the opioid antagonist comprises naltrexone. In someembodiments the naltrexone comprises a controlled-release naltrexone. Insome embodiments the controlled-release naltrexone comprises asustained-release naltrexone.

In some embodiments the first drug comprises an antidepressant and thesecond drug comprises an anticonvulsant. In some embodiments theantidepressant comprises bupropion and the anticonvulsant compriseszonisamide. In some embodiments the first drug comprises anantidepressant and the second drug comprises an opioid antagonist. Insome embodiments the antidepressant comprises bupropion and the opioidantagonist comprises naltrexone.

In some embodiments the method further comprises identifying the patientas being at risk of suffering an adverse side effect from administrationof an anticonvulsant. In some embodiments the method further comprisesidentifying the patient as being at risk of suffering an adverse sideeffect from administration of an opioid antagonist.

In some embodiments the method further comprises opening a unit dosagepackage, the unit dosage package comprising the first dosage and thesecond dosage. In some embodiments the unit dosage package comprises ablister pack. In some embodiments the method further comprisesadministering a third dosage comprising the first drug and the seconddrug, wherein the third dosage comprises a greater amount of the seconddrug than the second dosage. In some embodiments the method furthercomprises removing the first dosage and the second dosage from the unitdosage package. In some embodiments administering the first dosagecomprises administering a tablet that comprises the first drug and thesecond drug. In some embodiments the tablet comprises a plurality oflayers. In some embodiments the tablet is a trilayer tablet. In someembodiments a single blister comprises multiple drugs, wherein each drugis physically separated in physically separate forms, e.g, two or moretablets, capsules, pills, etc.

In some embodiments subsequent administrations of subsequentcombinations of the first drug and the second drug are administered. Insome embodiments each subsequent combination the dosage of the seconddrug is increased, e.g., increasing the dosage of the second drug ineach subsequent combination of the first drug and the second drug untila full dosage of the second drug is reached. In this manner, theindividual can become accustomed to a full dosage combination of thefirst drug and the second drug through the above method and avoid manyof the adverse side effects that could occur if the full dosage had beeninitially administered. Further, avoiding the adverse side effectsreduces premature abandonment of the obesity medication and increasesthe probability of effecting weight loss in the individual.

In an embodiment a unit dosage package for a pharmaceutical formulationcomprises a first unit dosage comprising a first drug and a second drug;a second unit dosage comprising the first drug and the second drug,wherein the second dosage comprises a different amount of the seconddrug than the first dosage; and a unit dosage package configured to holdthe first unit dosage and the second unit dosage.

In some embodiments the second dosage comprises a greater amount of thesecond drug than the first dosage. In some embodiments the first drugcomprises an antidepressant. In some embodiments the antidepressantcomprises bupropion. In some embodiments the bupropion comprises asustained-release bupropion. In some embodiments the second drugcomprises an anticonvulsant. In some embodiments the anticonvulsantcomprises zonisamide. In some embodiments the zonisamide comprises asustained-release zonisamide. In some embodiments the second drugcomprises an opioid antagonist. In some embodiments the opioidantagonist comprises naltrexone. In some embodiments the naltrexonecomprises a sustained-release naltrexone.

In some embodiments the first drug comprises an antidepressant and thesecond drug comprises an anticonvulsant. In some embodiments theantidepressant comprises bupropion and the anticonvulsant compriseszonisamide. In some embodiments the first drug comprises anantidepressant and the second drug comprises an opioid antagonist. Insome embodiments the antidepressant comprises bupropion and the opioidantagonist comprises naltrexone.

In some embodiments the unit dosage package comprises at least oneblister and the at least one blister holds both the first drug and thesecond drug. In some embodiments the unit dosage package comprises ablister pack. In some embodiments at least one of the first unit dosageand the second unit dosage is a multi-layer tablet that comprises thefirst drug and the second drug. In some embodiments the multi-layertablet is a trilayer tablet.

Thus, in some preferred embodiments, the multi-layer tablet is usefulfor the treatment of obesity and/or for affecting weight loss. Somepreferred embodiments comprise at least one of an antidepressant and ananticonvulsant. Other preferred embodiments comprise at least one of anantidepressant and an opioid receptor antagonist. Other preferredembodiments comprise at least one of an anticonvulsant and an opioidreceptor antagonist. Other preferred embodiments comprise at least oneof an anticonvulsant and an antidiabetic.

In some embodiments, one or more of the drugs comprises naltrexone andone or more of the drugs comprises fluoxetine. In another embodiment,one or more of the drugs comprises olanzapine and one or more of thedrugs comprises zonisamide. In another embodiment, one or more of thedrugs comprises metformin and one or more of the drugs compriseszonisamide. In another embodiment, one or more of drugs comprisesphentermine and one or more of the drugs comprise topiramate.

In some embodiments the presence of one drug in a pharmaceuticalformulation enhances the desired physiological effects and/or reducesundesired physiological effects of one or more other drugs in thepharmaceutical formulation. In some embodiments the presence of one ormore drugs in a pharmaceutical formulation enhances the desiredphysiological effects of the drugs over the additive physiologicaleffects of the one or more drugs in comparable pharmaceuticalformulations when administered alone.

Pharmaceutical formulations of any drug mentioned herein can beconfigured in various ways and in a variety of dosage forms to modify adissolution rate of the drug. For example, one type ofcontrolled-release pharmaceutical formulation is a sustained-releasepharmaceutical formulation. Sustained-release pharmaceuticalformulations can contain a variety of excipients, such as retardantexcipients (also referred to as release modifiers) and/or fillers thatare selected and incorporated into the formulation in such a way as toslow the dissolution rate of the formulation (and thereby slow thedissolution and/or release of the zonisamide) under in vivo conditionsas compared to an otherwise comparable immediate-release formulation.Thus, a “comparable” immediate-release formulation is one that issubstantially identical to the controlled-release formulation, exceptthat that it is configured to provide immediate-release instead ofcontrolled-release under substantially identical conditions.

The term “immediate-release” is used herein to specify a formulationthat is not configured to alter the dissolution profile of the activeingredient (e.g., zonisamide, bupropion, naltrexone, olanzapine,phentermine, topiramate, metformin, fluoxetine). For example, animmediate-release pharmaceutical formulation may be a pharmaceuticalformulation that does not contain ingredients that have been includedfor the purpose of altering the dissolution profile. Animmediate-release formulation thus includes drug formulations that takeless than 30 minutes for substantially complete dissolution of the drugin a standard dissolution test. A “standard dissolution test,” as thatterm is used herein, is a test conducted according to United StatesPharmacopeia 24th edition (2000) (USP 24), pp. 1941-1943, usingApparatus 2 described therein at a spindle rotation speed of 100 rpm anda dissolution medium of water, at 37° C., or other test conditionssubstantially equivalent thereto. The term “controlled-release” is usedherein in its ordinary sense and thus includes pharmaceuticalformulations that are combined with ingredients to alter theirdissolution profile. A “sustained-release” formulation is a type ofcontrolled-release formulation, wherein ingredients have been added to apharmaceutical formulation such that the dissolution profile of theactive ingredient is extended over a longer period of time than that ofan otherwise comparable immediate-release formulation. Acontrolled-release formulation thus includes drug formulations that take30 minutes or longer for substantially complete dissolution of the drugin a standard dissolution test, conditions which are representative ofthe in vivo release profile.

In an embodiment a method of packaging a combination of bupropion and atleast one of zonisamide and naltrexone comprises providing a unit dosagepackage that holds the bupropion and the at least one of the zonisamideand the naltrexone; and packaging administration instructions with theunit dosage package in a unit dosage package.

In some embodiments the bupropion comprises a sustained-releasebupropion. In some embodiments the zonisamide comprises asustained-release zonisamide. In some embodiments the naltrexonecomprises a sustained-release naltrexone. In some embodiments packagingadministration instructions in the unit dosage package comprisesprinting instructions onto the unit dosage package. In some embodimentsthe unit dosage package comprises a blister pack.

In some embodiments, the method is realized by a medical professionale.g., a physician or a hospital employee. The medical professionaladministers each dosage, a “unit dosage” (as defined herein), of thefirst drug and the second drug to the individual in need of suchtreatment. Each succeeding unit dosage combination contains an increaseddosage of the second drug until a full dosage of the first drug incombination with the second drug is reached.

In one embodiment of the method the medical professional employs a unitdosage package. The unit dosage package contains a number of “unitdosages”, each representing a single administration of a particularpharmaceutical formulation. In some embodiments the pharmaceuticalformulation comprises a specific combination of a first drug and asecond drug. The pharmaceutical formulation may be a single pill,capsule, tablet, etc. or may be a plurality of pills, capsules, tablets,etc. Each successive pharmaceutical formulation in a unit dosage packageramps up the dosage of the second drug until a full dosage is reached.In this manner, at a first administration a medical professional removesa first pharmaceutical formulation dosage from the unit dosage packageand administers the first dosage to an individual. At a secondadministration the medical professional removes a second pharmaceuticalformulation dosage from the unit dosage package and administers thesecond dosage to the individual. At subsequent administrations themedical professional removes and administers successive pharmaceuticalformulation dosages until a full dosage of the second drug incombination with the first drug is reached. The medical professional isthus able to perform one embodiment of the method.

Another embodiment provides a system for performing the method by anindividual without the constant supervision of a medical professional.An individual is provided with a unit dosage package comprising a unitdosage package. The unit dosage package comprises a number of dosages,each dosage representing a pharmaceutical formulation. Thepharmaceutical formulations comprise varying combinations of a firstdrug and a second drug. In preferred embodiments the dosages arearranged within the unit dosage package so that each successivepharmaceutical formulation contains increased amounts of the second drugin combination with constant amounts of the first drug e.g., until afull dosage of the second drug is reached. On a first day, theindividual removes the first pharmaceutical formulation from the unitdosage package and ingests it. On a second day, based on the structureof the unit dosage package, the individual removes a secondpharmaceutical formulation and ingests it. In some embodiments eachsuccessive dosage is labeled sequentially with numbers or letters, or acombination of the two. In some embodiments each successive dosagecorresponds to a day or time label. In preferred embodiments the secondpharmaceutical formulation and each successive formulation in the unitdosage package comprise an increased amount of the second drug until afull dosage is reached. Some embodiments of a unit dosage package alsocomprise instructions to the individual for administration of eachsuccessive pharmaceutical formulation. The individual becomes accustomedto increased pharmaceutical formulations dosages. Thus, the individualcan use the unit dosage package to decrease or avoid many of the initialadverse side effects associated with administering a full dosagecombination of the first drug and the second drug to affect weight loss.

It may be convenient for a consumer to have a unit dosage package thatdesignates a particular length of time for administration of one or moredrugs. For example, a particular unit dosage package may comprise amonth of unit dosages. Another unit dosage package may comprise a weekof unit dosages. Another unit dosage package may comprise two or moredays of unit dosages. A unit dosage package may also comprise detachablestrips representing smaller lengths of time. For example, a unit dosagepackage representing two or more weeks may comprise two or more portionsthat may be detached to form individual unit dosage packages.

Certain embodiments of unit dosage packages are known in the art. See,for example, U.S. Pat. No. 3,942,641, wherein it is indicated that unitdosage packages include those that accommodate pharmaceuticalformulations representing daily unit dosage forms in a contiguous,sequential arrangement which, if properly used according to instructionspackaged therewith, cause the proper formulation to be administered atthe appropriate time. For example, such a unit dosage package cancomprise individual blister pods (“blisters”) for the storage in each ofa single unit dosage form. At the appropriate time the unit dosage formis manually dispensed therefrom through a frangible retaining layer.Storage of other unit dosage forms is not affected by such dispensing.Appropriate notations are placed on the unit dosage package or the unitdosage package, if desired, to guide or instruct the user thereof in theproper use of the pharmaceutical formulations contained therein. Forexample, day of the week, miscellaneous instructions, etc., areprovided, if so desired.

In some embodiments a unit dosage package comprises a number ofblisters. Blisters comprise unit dosages. Unit dosages of pharmaceuticalformulations comprising at least a first drug and a second drug are thusadministered from the unit dosage package. In some embodiments, a singleblister contains a unit dosage of both the first drug and the seconddrug. In other embodiments a single blister contains either a unitdosage of a first drug or a unit dosage of a second drug. (In the lattercase a corresponding blister can contain a corresponding dosage of theother.)

In some embodiments a unit dosage package is a blister pack, a pill boxor a medication dispenser. Examples of pill boxes include a wallet cardpill carrier, a key ring pill box, a capsule shaped pill box, a hollownecklace dispenser, a weekly organizer, an organizer cube, an airtightbox and a hollow pocket watch. Examples of medication dispensers includecertain types of unit dosage packages that hold certain medications in aspecific order for accurate administration. In some embodiments a unitdosage package has compartments holding specific unit dosages and/orcombinations of pharmaceutical formulations including prescribedmedications suitable for administration to a patient. Some unit dosagepackages include instructions for medication administration.

In some embodiments, the dosages are provided at least once, twice orthree times a day for a set period, which can be at least, at leastabout, less than, less than about, equal to or between any range within1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 consecutive days or at least,at least about, less than, less than about, equal to or between anyrange within of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 consecutiveweeks or at least, at least about, less than, less than about, equal toor between any range within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30consecutive months. The amount of drug in any pharmaceutical formulationdescribed herein includes amounts of at least, at least about, lessthan, less than about, equal to or between any range within 0.01, 0.02,0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200,250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900,950, 1000, 1500, 2000, 3000, 4000 or 5000 mg.

In one embodiment a unit dosage package for a pharmaceuticalformulation, comprises a first unit dosage comprising a first drug and asecond drug, a second unit dosage comprising the first drug and thesecond drug, wherein the second unit dosage comprises a different amountof the second drug than the first unit dosage and a unit dosage packageconfigured to hold the first unit dosage and the second unit dosage.

In some embodiments the second unit dosage comprises a greater amount ofthe second drug than the first unit dosage. In some embodiments thefirst drug or the second drug comprises an antidepressant. In someembodiments the antidepressant comprises bupropion. In some embodimentsthe bupropion comprises a sustained-release bupropion. In someembodiments the first drug or the second drug comprises ananticonvulsant. In some embodiments the anticonvulsant compriseszonisamide. In some embodiments the zonisamide comprises asustained-release zonisamide. In some embodiments the first drug or thesecond drug comprises an opioid antagonist. In some embodiments theopioid antagonist comprises naltrexone.

In some embodiments the first drug comprises bupropion and the seconddrug comprises zonisamide. In some embodiments the first drug comprisesbupropion and the second drug comprises naltrexone. In some embodimentsthe first drug comprises fluoxetine and the second drug comprisesnaltrexone. In some embodiments the first drug comprises olanzapine andthe second drug comprises zonisamide. In some embodiments the first drugcomprises antidiabetic and the second drug comprises zonisamide. In someembodiments the antidiabetic comprises metformin. In some embodimentsthe first drug comprises topiramate and the second drug comprisesphentermine. In some embodiments the unit dosage package comprises ablister and the blister holds both the first drug and the second drug.

In some embodiments the first drug and the second drug are selected fromthe group consisting of zonisamide, bupropion, naltrexone, phentermine,topiramate, metformin, olanzapine, fluoxetine, and any combinations,prodrugs or salts thereof. In some embodiments the first drug and thesecond drug are part of a single physical form. In some embodiments thesingle physical form is a multi-layer tablet. In some embodiments themulti-layer tablet is a trilayer tablet. In some embodiments the unitdosage package comprises a first blister and a second blister, whereinthe first blister holds the first drug and the second blister holds thesecond drug. In some embodiments the unit dosage package comprises ablister pack.

In one embodiment a method of providing a pharmaceutical formulation toa patient comprises providing a unit dosage package for a pharmaceuticalformulation, wherein the unit dosage package is configured to hold afirst unit dosage and a second unit dosage, wherein the first unitdosage comprises a first drug and a second drug, wherein the second unitdosage comprises the first drug and the second drug, and wherein thesecond unit dosage comprises a different amount of the second drug thanthe first unit dosage.

In some embodiments the method further comprises identifying a patientwith an obesity related condition, wherein the obesity-related conditionis selected from the group consisting of obesity, hypertension,diabetes, dyslipidaemia, weight gain associated with smoking cessationand weight gain associated with use of a psychotherapeutic drug. In someembodiments the second dosage comprises a greater amount of the seconddrug than the first dosage.

In some embodiments the first drug or the second drug comprises anantidepressant. In some embodiments the first drug or the second drugcomprises an anticonvulsant. In some embodiments the first drug or thesecond drug comprises an opioid antagonist. In some embodiments thefirst drug or the second drug comprises an antidiabetic. In someembodiments the first drug and the second drug are selected from thegroup consisting of zonisamide, bupropion, naltrexone, phentermine,topiramate, antidiabetic, olanzapine, fluoxetine, and any combinations,prodrugs or salts thereof.

In some embodiments the method further comprises identifying the patientas being at risk of suffering an adverse side effect from administrationof an anticonvulsant. In some embodiments the method further comprisesidentifying the patient as being at risk of suffering an adverse sideeffect from administration of an opioid antagonist. In some embodimentsthe method further comprises opening a unit dosage package, the unitdosage package comprising the first dosage and the second dosage. Insome embodiments the unit dosage package comprises a blister pack.

In some embodiments the unit dosage package comprises a third unitdosage and, wherein the third dosage comprises a greater amount of thesecond drug than the second dosage. In some embodiments providing theunit dosage package comprises removing the first dosage and the seconddosage from the unit dosage package. In some embodiments providing aunit dosage package comprises administering a tablet that comprises thefirst drug and the second drug to the patient, wherein the tabletcomprises a plurality of layers. In some embodiments the tablet is atrilayer tablet.

It will be appreciated by those skilled in the art that variousmodifications and changes can be made without departing from the scopeof the invention. Such modifications and changes are intended to fallwithin the scope of the invention, as defined by the appended claims.

What is claimed is:
 1. A method of administering a pharmaceuticalformulation to an individual, comprising: administering a first amountof a pharmaceutical formulation every day for a first week, wherein thefirst amount of a pharmaceutical formulation comprises about 90 mg ofbupropion and an amount of naltrexone selected from the group consistingof about 4 mg and about 8 mg; administering a second amount of apharmaceutical formulation every day for a second week, wherein thesecond amount of a pharmaceutical formulation comprises bupropion andnaltrexone, and wherein the second amount of a pharmaceuticalformulation comprises about twice as much bupropion and about twice asmuch naltrexone as the first amount of a pharmaceutical formulation;administering a third amount of a pharmaceutical formulation every dayfor a third week, wherein the third amount of a pharmaceuticalformulation comprises bupropion and naltrexone, and wherein the thirdamount of a pharmaceutical formulation comprises about three times asmuch bupropion and about three times as much naltrexone as the firstamount of a pharmaceutical formulation; and administering a fourthamount of a pharmaceutical formulation every day for a fourth week,wherein the fourth amount of a pharmaceutical formulation comprisesbupropion and naltrexone, and wherein the fourth amount of apharmaceutical formulation comprises about four times as much bupropionand about four times as much naltrexone as the first amount of apharmaceutical formulation.
 2. The method of claim 1, wherein the firstamount of a pharmaceutical formulation comprises about 8 mg naltrexone.3. The method of claim 1, wherein the first amount of a pharmaceuticalformulation comprises about 4 mg naltrexone.
 4. The method of claim 1,wherein the first amount of a pharmaceutical formulation is in a singleoral dosage form.
 5. The method of claim 4, wherein the single oraldosage form is selected from the group consisting of a tablet, a pilland a capsule.
 6. The method of claim 4, wherein the second amount of apharmaceutical formulation comprises two of the single oral dosageforms.
 7. The method of claim 6, wherein the third amount of apharmaceutical formulation comprises three of the single oral dosageforms.
 8. The method of claim 7, wherein the fourth amount of apharmaceutical formulation comprises four of the single oral dosageforms.
 9. The method of claim 1, wherein the bupropion is in a sustainedrelease formulation and the naltrexone is in a sustained releaseformulation.
 10. The method of claim 9, wherein the first amount of apharmaceutical formulation is in a single oral dosage form, wherein thesecond amount of a pharmaceutical formulation comprises two of thesingle oral dosage forms, wherein the third amount of a pharmaceuticalformulation comprises three of the single oral dosage forms, and whereinthe fourth amount of a pharmaceutical formulation comprises four of thesingle oral dosage forms.
 11. The method of claim 10, wherein the singleoral dosage form is a multilayer tablet comprising a firstpharmaceutical layer comprising the sustained release formulation ofbupropion and a second pharmaceutical layer comprising the sustainedrelease formulation of naltrexone, and an intermediate layer between thefirst and the second pharmaceutical layers, wherein the intermediatelayer is configured to dissolve rapidly in vivo.
 12. The method of claim9, wherein the first amount of a pharmaceutical formulation consists oftwo single oral dosages forms, the sustained release bupropion in afirst single oral dosage form and the sustained release naltrexone in asecond single oral dosage form, wherein the second amount of apharmaceutical formulation consists of two of the first single oraldosage forms and two of the second single oral dosage forms, wherein thethird amount of a pharmaceutical formulation consists of three of thefirst single oral dosage forms and three of the second single oraldosage forms, and wherein the fourth amount of a pharmaceuticalformulation consists of four of the first single oral dosage forms andfour of the second single oral dosage forms.
 13. The method of claim 9,wherein the first amount of a pharmaceutical formulation consists of twosingle oral dosages forms, the sustained release bupropion having afirst single oral dosage form and the sustained release naltrexonehaving a second single oral dosage form, wherein the second amount of apharmaceutical formulation consists of two single oral dosages forms,the sustained release bupropion having a third single oral dosage form,and the sustained release naltrexone having a fourth single oral dosageform, and wherein the third amount of a pharmaceutical formulationconsists of two single oral dosages forms, the sustained releasebupropion having the first single oral dosage form and the third singleoral dosage form, and the sustained release naltrexone having the secondsingle oral dosage form and the fourth single oral dosage form, whereinthe fourth amount of a pharmaceutical formulation consists of two of thethird single oral dosage forms and two of the fourth single oral dosageforms.
 14. The method of claim 1, further comprising identifying saidindividual as obese, and said administering of said pharmaceuticalformulation is for treatment of obesity.
 15. The method of claim 10,further comprising identifying said individual as obese, and saidadministering of said pharmaceutical formulation is for treatment ofobesity.
 16. The method of claim 11, further comprising identifying saidindividual as obese, and said administering of said pharmaceuticalformulation is for treatment of obesity.
 17. A method of administering apharmaceutical formulation to an obese individual, comprising:identifying an individual as obese; providing to the individual a firstamount of a pharmaceutical formulation for daily administration during afirst week, wherein the first amount of a pharmaceutical formulationcomprises about 90 mg of bupropion and an amount of naltrexone selectedfrom the group consisting of about 4 mg and about 8 mg, wherein thebupropion is in a sustained release formulation and the naltrexone is ina sustained release formulation, and wherein the first amount of apharmaceutical formulation is in a single oral dosage form; providing tothe individual a second amount of a pharmaceutical formulation for dailyadministration during a second week, and wherein the second amount of apharmaceutical formulation comprises about twice as much bupropion andabout twice as much naltrexone as the first amount of a pharmaceuticalformulation; providing to the individual a third amount of apharmaceutical formulation for daily administration during a third week,wherein the third amount of a pharmaceutical formulation comprises aboutthree times as much bupropion and about three times as much naltrexoneas the first amount of a pharmaceutical formulation; and providing tothe individual a fourth amount of a pharmaceutical formulation for dailyadministration during a fourth week, wherein the fourth amount of apharmaceutical formulation comprises about four times as much bupropionand about four times as much naltrexone as the first amount of apharmaceutical formulation, and wherein the providing of the firstamount of a pharmaceutical formulation, the second amount of apharmaceutical formulation, the third amount of a pharmaceuticalformulation and the fourth amount of a pharmaceutical formulation arefor treatment of obesity.